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. 2020 Nov 5;13(11):366.
doi: 10.3390/ph13110366.

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

Jérémy P Schneider  1 , Stefano Tommasone  2 , Paolo Della Sala  2 , Carmine Gaeta  2 , Carmen Talotta  2 , Céline Tarnus  3 , Placido Neri  2 , Anne Bodlenner  1 , Philippe Compain  1
Affiliations

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

Jérémy P Schneider et al. Pharmaceuticals (Basel). .

Abstract

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ Ki being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes.

Keywords: CuAAC; calix[8]arene; inhibitory multivalent effect; multivalency; α-mannosidase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure and inhibition constant against Jack Bean α-mannosidase of multivalent clusters and their monovalent references.
Figure 2
Figure 2
Calix[8]arene based multivalent clusters 6a–c and 7a–c. For a full picture of those compounds see SI Figures S1–S6.
Scheme 1
Scheme 1
Preparation of scaffolds 10 and 11. (i) Cs2CO3, acetone, reflux (10: 76%; 11: 57%).
Scheme 2
Scheme 2
Synthesis of multivalent clusters 6 and 7.
Figure 3
Figure 3
Docking experiments. (a,b) The 3D model of the binding mode of 7b with JBα-man. In (a) the ligand 7b is given in blue while the protein is colored in yellow. (b) Magnification of the interaction with ligand 7b. (c) Detailed view of the octahedral coordination of Zn ion (in magenta) in enzyme pocket: the coordination of Zn ion with the oxygen atoms of the iminosugar is highlighted. (d) Detailed view of the hydrophobic interactions between the lipophilic alkyl chain of the Zn-coordinated DNJ of cluster 7b with G788 and G790.
Figure 4
Figure 4
Docking experiments. The 3D model of the octopus-like binding mode of dendritic cluster 6c to JBα-man dimer. The calculation was performed on a simplified cluster model bearing four DNJ heads in order to overcome computing limitations found during the docking calculation with the complete 24-valent cluster 6c.
Figure 5
Figure 5
Docking experiments. (Left) Detail of the threading of a DNJ head (in red) of 6c with JBα-man (in yellow). (Right) Octahedral coordination of Zn ion (in magenta) in enzyme pocket: the coordination of Zn ion with the oxygen atoms of the iminosugar is highlighted.
See this image and copyright information in PMC

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